|Title||Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF-PU.1-DPP4 Axis.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||L Wang, E Wang, Prado J Balcazar, Z Wu, K Xiang, Y Wang, Q Huang, M Negrete, K-Y Chen, W Li, Y Fu, A Dohlman, R Mines, L Zhang, Y Kobayashi, T Chen, G Shi, JP Shen, S Kopetz, PR Tata, V Moreno, C Gersbach, G Crawford, D Hsu, E Huang, P Bu, and X Shen|
|Journal||Advanced Science (Weinheim, Baden Wurttemberg, Germany)|
Colorectal cancer (CRC) metastasizes mainly to the liver, which accounts for the majority of CRC-related deaths. Here it is shown that metastatic cells undergo specific chromatin remodeling in the liver. Hepatic growth factor (HGF) induces phosphorylation of PU.1, a pioneer factor, which in turn binds and opens chromatin regions of downstream effector genes. PU.1 increases histone acetylation at the DPP4 locus. Precise epigenetic silencing by CRISPR/dCas9KRAB or CRISPR/dCas9HDAC revealed that individual PU.1-remodeled regulatory elements collectively modulate DPP4 expression and liver metastasis growth. Genetic silencing or pharmacological inhibition of each factor along this chromatin remodeling axis strongly suppressed liver metastasis. Therefore, microenvironment-induced epimutation is an important mechanism for metastatic tumor cells to grow in their new niche. This study presents a potential strategy to target chromatin remodeling in metastatic cancer and the promise of repurposing drugs to treat metastasis.
|Short Title||Advanced Science (Weinheim, Baden Wurttemberg, Germany)|